The collagen VII (C7) protein is a structural protein in which C7 is both a structural and functional precursor for the formation of anchoring fibrils which enable the attachment of the epidermis and the dermis. The C7 monomer assembles as a homotrimer of approximately 900 kDa, containing one NC-1 and one NC-2 binding region. The homotrimer is held together via an alpha helical coil. From a homotrimer, these C7 protein precursors align into an anti-parallel dimer with an increase in molecular weight to 1.8 mDa. Lateral assembly of anti-parallel dimers leads to the formation of the anchoring fibrils. The rC7 protein demonstrates “stickiness,” and the propensity to precipitate at higher protein concentrations, particularly in PBS buffer.
Lack of C7 leads to abnormal decrease in these anchoring fibrils and a condition known as Dystrophic Epidermolysis Bullosa (DEB). EB encompasses a group of molecularly diverse diseases characterized by the development of blisters after minor mechanical trauma to the skin. (1) Severity, extracutaneous manifestations and clinical course depend on the type of EB; however, almost all patients experience blistering or ruptured skin. (2)
Dystrophic epidermolysis bullosa (DEB) is a form of EB characterized by development of scarring with healing. (3) In patients with DEB, blistering can be triggered by even minor mechanical trauma owing to the extremely fragile nature of the skin. This leads to a chronic cycle of blistering, healing, and reblistering that causes patients to suffer from painful wounds and debilitating scarring of epithelial tissue. There is no cure for DEB and management focuses on supportive care.
Dystrophic EB is caused by mutations in the Col7a1 gene, which encodes the alpha chain of collagen VII (C7), a protein essential for the formation of the anchoring fibrils that anchor the basement membrane to the underlying dermis. (4) The condition is inherited as either a dominant form (DDEB) or a recessive form (RDEB), with RDEB typically having a more severe phenotype. (5)
The DEB mouse model (Col7a1−/−) has a targeted inactivation of the Col7a1 gene, resulting in severe blistering that mimics the histological and ultrastructural presentation of severe human RDEB. (6) These mice have no detectable collagen VII at the dermal-epidermal basement membrane zone (BMZ), completely lack anchoring fibrils, and are born with extensive cutaneous blisters on their ventral surface and hemorrhagic blisters on their paws and neck, with mortality typically observed within the first week of life.